Ameliorant for chemical treatment of cancer

ABSTRACT

An ameliorating agent for cancer chemotherapy is disclosed, which comprises a chromanol glycoside represented by the following general formula (1) 
                         
(wherein R 1 , R 2 , R 3 , and R 4 , which are identical or different from each other, stand for a hydrogen atom or a lower alkyl group, R 5  stands for a hydrogen atom, a lower alkyl group, or a lower acyl group, X stands for a monosaccharide residue or an oligosaccharide residue optionally having the hydrogen atom of the hydroxyl group in the saccharide residue substituted with a lower alkyl group or a lower acyl group, n is an integer in the range of 0-6, and m is an integer in the range of 1-6).
 
     According to this invention, a novel ameliorating agent for cancer chemotherapy is provided which acts safely and effectively in a small dosage to enhance the carcinostatic action of an anti-cancer agent in cancer chemotherapy and repressing side effects by cancer chemotherapy as well.

TECHNICAL FIELD

This invention relates to a novel ameliorating agent for cancerchemotherapy. More particularly, this invention relates to anameliorating agent for cancer chemotherapy containing as an activeingredient a water-soluble chromanol glycoside.

BACKGROUND ART

Cancers have been a disease that occupies the first position in the listof causes of death of the Japanese since 1981 and the number of patientsof this disease has been increasing thence year after year. The basicresearch and clinical research regarding the therapy of cancer has beenadvancing on the global level over these 10-odd years. This developmentin association with the advance of the diagnosis of cancer has beenmaking it feasible to ensure early detection and treatment of a cancer.

The therapy of cancer is based on a surgical operation, a radiotherapy,and a cancer chemotherapy (therapy using an anti-cancer agent). Thecancer chemotherapy is a method for treating malignant neoplasm by theadministration of an anti-cancer agent. Since an anti-cancer agent hasno substantially different effects between cancer cells and normalcells, side effects thereof become severe in accordance with theimprovement of treatment effects. Cisplatin, for example, has seriousside effects such as renal dysfunction, nausea, vomiting, neuropathy,myelopathy like leukopenia, thrombocytopenia, and anaemia. Themanifestation of such side effects which are caused by the cancerchemotherapy often entail such a situation as limiting the dosage of ananti-cancer agent and discontinuing the therapy. Further, the restraintof the side effects has an important influence on the life lengtheningof a patient under treatment. In the execution of the cancerchemotherapy, therefore, it is a very important task to decrease theside effects without repressing the effects on the treatment with ananti-cancer agent.

As medicines for decreasing the side effects by the therapy with ananti-cancer agent, such 5-HT₃ acceptor antagonists as granisetron andondansetron which are effective for nausea and vomiting and such bonemarrow function activators as filgrastim and lenograstim which areeffective for leukopenia have been known. In the field of cancerchemotherapy, the desirability for developing a novel ameliorating agentfor cancer chemotherapy which enhances the carcinostatic action of ananti-cancer agent and represses various side effects thereof has beenstill finding popular recognition.

The chromanol glycoside which is used in this invention is a knowncompound (JP-A-7(1995)-118287, JP-A-9(1997)-249688, andJP-A-11(1999)-21291). The chromanol glycoside results from substitutingan alcohol for the phytyl group at the 2 position of a chroman ring of arepresentative example of Vitamin E, α-tocopherol, and further linkingsaccharide thereto and has high water-solubility and excellentantioxidizing ability. The use of this chromanol glycoside as anameliorating agent for the cancer chemotherapy, however, has never beenknown heretofore.

This invention has been attained in consideration of the problems of theprior art as described above. It is an object of this invention toprovide a novel ameliorating agent for cancer chemotherapy whicheffectively functions safely in a small amount and exhibits excellentability of repressing various side effects entailed by the cancerchemotherapy.

Another object of this invention is to provide a novel amelioratingagent for cancer chemotherapy which enhances carcinostatic function ofan anti-cancer agent in the cancer chemotherapy.

DISCLOSURE OF THE INVENTION

The present inventors, after repeating a diligent study in search of anagent for repressing side effects by cancer chemotherapy, have foundthat the chromanol glycoside mentioned above can not only enhancecarcinostatic function of an anti-cancer agent but also repress trulyeffectively various side effects entailed by the cancer chemotherapy.This invention has been perfected as a result.

To be specific, this invention is to provide an ameliorating agent forcancer chemotherapy which comprises a chromanol glycoside represented bythe following general formula (1)

(wherein R¹, R², R³, and R⁴, which are identical or different from eachother, stand for a hydrogen atom or a lower alkyl group, R⁵ stands for ahydrogen atom, a lower alkyl group, or a lower acyl group, X stands fora monosaccharide residue or an oligosaccharide residue optionally havingthe hydrogen atom of the hydroxyl group in the saccharide residuesubstituted with a lower alkyl group or a lower acyl group, n is aninteger in the range of 0-6, and m is an integer in the range of 1-6).

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above which is an agent for repressing sideeffects.

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above which is an agent for enhancingcarcinostatic action.

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above, wherein the cancer chemotherapy is atherapy by the use of a cytotoxic anti-cancer agent.

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above, wherein the cytotoxic anti-cancer agent isan alkylating agent, an antineoplastic vegetable component-containingpreparation, an antineoplastic antibiotic preparation, or a DNAchelating agent.

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above, wherein the cytotoxic anti-cancer agent iscisplatin, cyclophosphamide, or doxorubicin hydrochloride.

This invention also concerns an ameliorating agent for cancerchemotherapy mentioned above, wherein the chromanol glycoside mentionedabove is 2-(α-D-glucopyranocyl)methyl-2,5,7,8-tetramethyl chroman-6-ol.

This invention also concerns an ameliorating agent for cancerchemotherapy which is a water-soluble preparation.

BEST MODE OF CARRYING OUT THE INVENTION

The ameliorating agent for cancer chemotherapy of this invention ischaracterized by having as an active ingredient thereof a chromanolglycoside represented by the aforementioned general formula (1).

In the general formula (1) mentioned above, the lower alkyl groupsrepresented by R¹, R², R³, R⁴ and R⁵ include suitably lower alkyl groupsof 1-8, preferably 1-6, carbon atoms. As typical examples thereof,methyl group, ethyl group, propyl group, isoproplyl group, butyl group,isobutyl group, pentyl group, isopentyl group, hexyl group, heptylgroup, and octyl group may be cited. Among these groups, methyl group orethyl group proves particularly advantageous. The lower acyl groupsrepresented by R⁵ include suitably lower acyl groups of 1-8, preferably1-6, carbon atoms. As typical examples thereof, formyl group, acetylgroup, propionyl group, butyryl group, isobutyryl group, valeryl group,isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group, andoctanoyl group may be cited. Among these lower acyl groups, acetylgroup, propionyl group, or butyryl group proves particularlyadvantageous. As typical examples of the monosaccharide residuerepresented by “X”, saccharide residues such as of glucose, galactose,fucose, xylose, mannose, rhamnose, fructose, arabinose, lyxose, ribose,allose, altrose, idose, talose, deoxyribose, 2-deoxyribose, quinovose,and abequose may be cited. The oligosaccharide residue represented by“X” includes residues of oligosaccharide having two to fourmonosaccharides as mentioned above combined such as, for example,maltose, lactose, cellobiose, raffinose, xylobiose, and sucrose. Amongthese saccharide residues, suchmonosaccharide residues as of glucose,galactose, fucose, xylose, rhamnose, mannose, and fructose proveparticularly advantageous. The hydrogen atom of the hydroxyl group inthe saccharide residue represented by “X” may be substituted with alower alkyl group, preferably a lower alkyl group of 1-8 carbon atoms,or a lower acyl group, preferably a lower acyl group of 1-10 carbonatoms. Further, n is an integer in the range of 0-6, preferably 1-4 andm is an integer in the range of 1-6, preferably 1-3. As preferredexamples of the chromanol glycoside represented by the general formula(1), 2-(α-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol,2-(β-D-galactopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol,2-(β-L-fucopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol,2-(α-L-rhamnopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol,2-(β-D-xylopyranosyl)methyl-2,5,7,8-tettramethyl chroman-6-ol,2-(β-D-glucopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol,2-(β-D-fructofuranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol, and2-(α-D-mannopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol may becited.

The chromanol glycoside which can be used in this invention may beproduced by an enzymatic reaction (enzyme method) which comprisesreacting a 2-substituted alcohol represented by the following generalformula (2):

(wherein R¹, R², R³, R⁴, R⁵ and n are as defined above) with anoligosaccharide in the presence of an enzyme capable of promoting therelevant saccharide transition thereby linking a specific hydroxyl groupof the saccharide specifically to the hydroxyl group at the 2 positionof the 2-substituted alcohol, in accordance with the methods disclosedin JP-A-7(1995)-118287, JP-A-9(1997)-249688, and JP-A-11(1999)-21291,for example.

The 2-substituted alcohol represented by the general formula (2) whichis used as one of the raw materials in the reaction mentioned above(hereinafter referred to simply as “2-substituted alcohol”) is a knownsubstance and can be obtained by the method disclosed inJP-B-1(1989)-43755 and JP-B-1(1989)-49135, for example. The2-substituted alcohol of the general formula (2) wherein R¹, R², R³, andR⁴ are a methyl group, R⁵ is a hydrogen atom, and n is 1, for example,can be easily obtained as by heating and refluxing6-hydroxy-2,5,7,8-tetramethyl chroman-2-carboxylic acid (commercialproduct “Trolox”) having a structure resulting from substituting acarboxyl group for a phythyl group at the 2 position of the chroman ringof α-tocopherol in diethyl ether in the presence of lithium aluminumhydride.

The chromanol glycoside used in this invention can be otherwise producedby subjecting to condensation reaction the 2-substituted alcoholmentioned above having the hydroxyl group at the 6 position thereofprotected with a protecting group and a saccharide derivative resultingfrom introducing a leaving group into the anomer position and protectingthe other hydroxyl groups with a protecting group in accordance with themethod disclosed in Japanese Patent Application No. 10-75599.

The chromanol glycoside according to this invention is a water-solublevitamin E having lipophilic property. Unlike the conventional vitamin Ederivatives which are insoluble in water or poorly soluble in water, thechromanol glycoside according to this invention, therefore, retains thelipophilic property even when it is used as dissolved in water and isconsequently capable of permeating a cell membrane and entering a cell.Consequently, the chromanol glycoside can not only enhance effects oftreatment with an anti-cancer agent but also repress effectively variousside effects which are associated with the cancer chemotherapy. Further,the chromanol glycoside which is obtained by the reaction as mentionedabove has significantly improved thermal stability and pH stability ascompared with tocopherol, Trolox, or 2-substituted alcohol.

The ameliorating agent of this invention for the cancer chemotherapy canbe used as a carcinostatic action-enhancing agent for enhancing thecarcinostatic action of an anti-cancer agent in the cancer chemotherapyand as a side effect-repressing agent for repressing the side effectsaccompanied with the cancer chemotherapy.

The cancerous diseases in this invention include brain tumor, carcinomaof head and neck, gastric cancer, colon cancer, hepatic cancer, biliarytract cancer, pancreatic cancer, lung cancer, breast cancer, uterinecancer, ovarian cancer, prostatic cancer, bladder cancer, human bone andsoft-tissue tumor, and leukemia, for example.

The term “cancer chemotherapy” as used in this invention refers to atherapy of cancer by the administration of an anti-cancer agent. Astypical examples of the anti-cancer agent, cytotoxic anti-cancer agentssuch as an alkylating agent, an antineoplastic vegetablecomponent-containing preparation, an antineoplastic antibioticpreparation, and a DNA chelating agent (a platinum compound) may becited. As typical examples of the alkylating agent, chloroethyl aminetype compounds such as cyclophosphamide, imidazol carboxamide, nitrogenmustard-N-oxide hydrochloride, melphalan, and ifosfamide, aziridine(ethyleneimine) type compounds such as carboquone and triethylenethiophospharamide, sulfonic ester type compounds such as busulfan andisoprosulfan tosylate, epoxide type compounds such as mitobronitol,nitrosourea type compounds such as nimustine and ranimustine,estramustine sodium phosphate may be cited. As typical examples of theantineoplastic vegetable component-containing preparation, vincaalkaloid preparations such as vincristine sulfate, vinblastine sulfate,and vindesine sulfate, podophyllin preparations such as etoposide, andirinotecan hydrochloride may be cited. As typical examples of theantineoplastic antibiotic preparation, anthracyclines such asdoxorubicin hydrochloride (adriamycin), idarubicin hydrochloride,daunorubicin hydrochloride, aclarubicin Hydrochloride, epirubicinhydrochloride, and purarubicin hycrochlooride, pleomycins such aspleomycin and peplomycin sulfate, mitomycins such as mitomycin C,actinomycins such as actinomycin D, zinostatinstimalamer, andpolypeptides such as neocarzinostatin may be cited. As typical examplesof the DNA chelating agent (platinum compound), cisplatin, carboplatin,and nedaplatin may be cited. As typical examples of other anti-canceragents, sobuzoxane, tretinoin, pentostatin, L-asparaginase, flutamide,porphimer natrium, fadrozole hydrochloride, procarbazine hydrochloride,aceglatone, and mitoxantrone hydrochloride may be cited.

The side effects of the cancer therapy to which the ameliorating agentof this invention for cancer chemotherapy can apply include myelopathylike leukopenia, granulocytopenia, lymphopenia, thrombocytopenia, anderythropenia, hematopathy such as plasma fibrinogenopenia, digestivedisorders such as nausea, vomiting, anorexia, heavy feeling of stomach,diarrhea, constipation, stomatitis, and esophagitis, pulmonaryinsufficiency such as chronic pneumonia and lung fibrosis, dermatopathysuch as keratinization, pachymenia, chromatosis, epilation, rash, andnail alternation, nervous system disorder such as paresthesia, deepareflexia, neuroparalysis, auditory disorder, allolalia, disorientation,neurologic manifestation, cerebellar ataxia, somnolence, coma, vertigo,frequency of micturition, and frequency of defecation desire, endocrinedisorder such as pituitary disorder, adrenal disorder, hyperglycemia,and hypoglycemia, genital disorder such as hyposexuality, oligospermia,gynecomastia menstrual disorder, cardiovascular disorder such ascardiomyopathy, arrhythmia, low blood pressure, tachycardia, and cardiacfailure, hepatopathy, pancreatic disorder, nephropathy, bladder trouble,hyperuricemia, decrease of immunocompetence, and infection which aremanifested in consequence of the cancer therapy mentioned above.

The ameliorating agent of this invention for the cancer chemotherapy maybe administered either orally or parenterally prior to, during, or afterthe execution of the cancer chemotherapy by using the chromanolglycoside mentioned above either singly or as formulated with apharmaceutically acceptable carrier or in the form of a compositionhaving the chromanol glycoside dissolved or suspended in apharmaceutically acceptable solvent.

When the ameliorating agent is used for the oral administration, thechromanol glycoside mentioned above may be used either singly or in theform of a solid preparation including tablet, powdered drug (powder),pill, or granules obtained by properly mixing the chromanol glycosidewith a suitable additive such as, for example, an excipient likelactose, sucrose, mannitol, cornstarch, synthetic or natural rubber, andcrystalline cellulose, a binder like starch, cellulose derivative, gumArabic, gelatin, and polyvinyl pyrrolidone, a disintegrator like carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, cornstarch, and sodium alginate, a lubricant like talc, magnesium stearate,and sodium stearate, a filler or diluent like calcium carbonate, sodiumcarbonate, calcium phosphate, and sodium phosphate. It may be used in acapsule form by using a hard or soft gelatin capsule. The solidpreparation may be applied with an enteric coating by using a coatingbase such as hydroxypropyl methyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate phthalate, andmethacrylate copolymer. Further, the chromanol glycoside mentioned abovemay be used in a liquid preparation such as a syrup or an elixir bydissolving it in an ordinarily used inert diluent such as purified waterand physiological saline and optionally adding the resultant solutionwith a wetting agent, an emulsifier, a dispersion auxiliary, asurfactant, a sweetener, a flavor, and a flavoring agent.

When the ameliorating agent for the cancer chemotherapy of thisinvention is to be used for the parenteral administration, the chromanolglycoside may be intravenously, subcutaneously, or intramuscularlyinjected in the form of a sterilized aqueous solution, non-aqueoussolution, suspension, liposome, or emulsion having the chromanolglycoside combined properly with a purified water, or a suitable buffersolution such as phosphate buffer, physiological salt solution such asphysiological saline, Ringer's solution, and Locke solution, ethanol,glycerin, and a commonly used surfactant, preferably in the form of asterilized aqueous solution for injection. The liquid preparation usedin this case properly has a physiological pH, preferably a pH in therange of 6-8. The ameliorating agent for the cancer chemotherapy of thisinvention may be percutaneously administered to a target site or theperipheral site thereof in the form of a liquid preparation such aslotion, suspension, or emulsion, a semi-solid preparation such as gel,cream, or ointment, or a solid preparation such as powder, dustingpowder, or granule which is dissolved prior to actual application. Itmay be otherwise implanted in the form of a pellet or administered inthe form of a suppository by using a suppository base. The form ofpreparation and the mode of administration can be properly selected by aphysician in charge of the therapy.

Although the concentration of the chromanol glycoside to be contained inthe ameliorating agent for the cancer chemotherapy of this invention maybe varied with the mode of administration, the kind of disease, theseriousness of the disease, and the dosage, it is generally in the rangeof 0.1-100 mass %, preferably 1-90 mass %, based on the total mass ofthe raw materials. Particularly when the preparation of this inventionis orally administered, the concentration is in the range of 1-100 mass%, preferably 5-90 mass %, based on the total mass of the raw materials.When it is parenterally administered, the concentration is in the rangeof 0.1-90 vol %, preferably 1-80 vol %, based on the total volume of theraw materials. In this case, if the concentration of the chromanolglycoside exceeds the upper limit of the range as specified above, theexcess would disadvantageously fail to bring a proportionate addition tothe repressing effects aimed at. Conversely, if the concentration isless than the lower limit of the range, the shortage would alsodisadvantageously result in preventing the repressing effect from beingmanifested fully satisfactorily.

The dosage of the ameliorating agent for the cancer chemotherapy of thisinvention may be varied depending on the age, body weight, and symptomof a patient, the mode and method of administration aimed at, theeffects of therapy, and the duration of treatment, and should beaccurately decided by the physician. Generally, the dose in the bothcases for oral and parenteral administration is in the range of0.01-2000 mg/kg of body weight as reduced to the dosage of chromanolglycoside.

The effects for enhancing the carcinostatic action and the effects forrepressing side effects in the cancer chemotherapy using theameliorating agent of this invention were confirmed by the followingpharmacological test.

As the chromanol glucoside,2-(α-D-glucopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol (TMG)represented by the following formula (3) which is produced by the methoddescribed in Example 1 of JP-A-7(1995)-118287 was used.

Confirmation Test for Effects of Enhancing Carcinostatic Action inCancer Chemotherapy (1)

P388 leukemia cells (6×10⁶ cells) were administered intraperitoneally tofemale BDF mice of 8-9 weeks old (8 heads per group, body weight of20-22 g). On the following day, a solution having prescribed amounts ofcisplatin (CDDP) and TMG in 0.2 ml of physiological saline wasintraperitoneally administered to the mice. The survival ratio of thesemice was measured 60 days after the administration of CDDP and TMG. Theresults are shown in Table 1.

TABLE 1 Dosage Number Survival (mg/kg) surviving ratio CDDP TMGAdministration Date (Heads) (%) 0 0 — 0 0 0 0.01 Every day from1^(st)-9^(th) days 0 0 0 0.1 Every day from 1^(st)-9^(th) days 0 0 0 1Every day from 1^(st)-9^(th) days 0 0 2 0 1^(st), 3^(rd), 5^(th), and7^(th) days 6 75 2 0.01 CDDP: 1^(st), 3^(rd), 5^(th), and 7^(th) days 8100 TMG: Every day from 1^(st)-9^(th) days 2 0.1 CDDP: 1^(st), 3^(rd),5^(th), and 7^(th) days 8 100 TMG: Every day from 1^(st)-9^(th) days 2 1CDDP: 1^(st), 3^(rd), 5^(th), and 7^(th) days 8 100 TMG: Every day from1^(st)-9^(th) days 4 0 1^(st), 5^(th), and 9^(th) days 6 75 4 0.01 CDDP:1^(st), 5^(th), and 9^(th) days 7 87.5 TMG: Every day from 1^(st)-9^(th)days 4 0.1 CDDP: 1^(st), 5^(th), and 9^(th) days 7 87.5 TMG: Every dayfrom 1^(st)-9^(th) days 4 1 CDDP: 1^(st), 5^(th), and 9^(th) days 8 100TMG: Every day from 1^(st)-9^(th) days

The results of Table 1 indicate that TMG has action for enhancing thecarcinostatic action of CDDP.

Confirmation Test for Effects of Enhancing Carcinostatic Action inCancer Chemotherapy (2)

P388 leukemia cells (6×10⁶ cells) were administered intraperitoneally tofemale BDF mice of 8-9 weeks old (8 heads per group, body weight of20-22 g). On the following day (1^(st) day), cyclophosphamide (CPA) andTMG were administered at respective dose of 360 mg/kg and 0.01 mg/kgwere intraperitoneally administered to the mice. Thereafter, CPA (360mg/kg) was administered on the 3^(rd), 5^(th), and 7^(th) days and TMG(0.01 mg/kg) was administered every day from the 2^(nd) through 9^(th)days. The survival ratio of these mice was measured 60 days after theadministration of CPA and TMG. The results are shown in Table 2.

TABLE 2 Number surviving Survival ratio Administration method (Heads)(%) No administration 0 0 CPA alone administered 4 50 TMG aloneadministered 0 0 CPA and TMG administered 6 75 simultaneously TMGadministered 5 hours before 8 100 administration of CPA

The results of Table 2 indicate that TMG has action for enhancing thecarcinostatic action of CPA.

Confirmation Test for Effects of Enhancing Carcinostatic Action inCancer Chemotherapy (3)

P388 leukemia cells (6×10⁶ cells) were administered intraperitoneally tofemale BDF mice of 8-9 weeks old (8 heads per group, body weight of20-22 g). On the following day (1^(st) day), 16 mg/kg of adriamycin(ADM) and a prescribed amount TMG were intraperitoneally administered tothe mice. Thereafter, ADM (16 mg/kg) was administered on the 3^(rd),5^(th), and 7^(th) days and TMG (prescribed amount as mentioned above)was simultaneously administered every day on the 2^(nd)-7^(th) days. Thesurvival ratio of these mice was measured 7 days after theadministration of ADM and TMG. The results are shown in Table 3.

TABLE 3 Dosage of TMG Number surviving Survival ratio (mg/kg) (Heads)(%) 0 0 0 0.1 5 62.5 1.0 3 37.5 10 1 12.5 500 1 12.5

The results of Table 3 indicate that the carcinostatic action by ADM issignificantly enhanced by the simultaneous administration with TMG.Further, it is indicated that the small dosage of TMG is more activethan the large dosage of TMG.

Confirmation Test for Effects of Repressing Side Effects in CancerChemotherapy (1)

CDDP was intraperitoneally administered in a dosage of 16 mg/kg, alethal dose, to 10 BDF mice of 8 weeks old (22-25 g). These mice formedControl Group. A group of mice to which CDDP was administeredsimultaneously with TMG in a dosage of 0.01 mg/kg formed Test Group 1and a group of mice to which CDDP was administered simultaneously withTMG in a dosage of 1.0 mg/kg formed Test Group 2. The time coursechanges of survival ratio of the Control Group and Test Groups weremeasured. The results are shown in Table 4.

TABLE 4 Days after administration Survival ratio (%) of CDDP ControlGroup Test Group 1 Test Group 2 0 100 100 100 5 80 100 100 8 30 100 5010 0 100 50

The results of Table 4 indicate that the groups involving additionaladministration of TMG show decreased toxicity of CDDP and a decreaseddeath ratio of mice, as compared with the Control Group, and that TestGroup 1 involving a smaller dosage manifests more outstanding effects.

Confirmation Test for Effects of Repressing Side Effects in CancerChemotherapy (2)

CDDP was intraperitoneally administered in a dosage of 2 mg/kg to 5 BDFmice of 8 weeks old once daily for 10 days. These mice formed ControlGroup. A group of mice to which CDDP was administered simultaneouslywith TMG in a dosage of 1 mg/kg once daily for 10 days formed TestGroup.

The time course changes of the numbers of leukocytes in blood of theControl Group and Test Group were measured. The results are shown inTable 5.

TABLE 5 Number of leukocytes Days after the (×10⁴/μl) start of testControl Group Test Group 0 2.0 2.0 10 1.0 1.1 20 0.6 1.3 25 1.1 2.0

The results of Table 5 indicate that the group involving TMGadministration shows very fast recovery of the number of leukocytes, ascompared with the Control Group.

Confirmation Test for Effects of Repressing Side Effects in CancerChemotherapy (3)

CDDP was intraperitoneally administered in a dosage of 16 mg/kg, alethal dose, to female BDF mice of 8-9 weeks old (8 heads per group,body weight of 20-22 g). After prescribed time therefrom, TMG wasadministered in a dosage of 0.01 mg/kg. After the elapse of 10 days, themortalities of these mice were measured. The results are shown in Table6.

TABLE 6 Interval of TMG administration Survival ratio after after CDDPadministration (hr) 10 days (%)  0 100 (Simultaneous administration)  575 10 0

The results of Table 6 indicate that the detoxication effects areimproved as the interval between the administration of CDDP and theadministration of TMG decreases, and that the simultaneousadministration with CDDP was most effective.

Confirmation Test for Effects of Repressing Side Effects in CancerChemotherapy (4)

P388 leukemia cells (6×10⁶ cells) were administered intraperitoneally tofemale BDF mice of 8-9 weeks old (8 heads per group, body weight of20-22 g). On the following day, ADM was administered in a dosage of 16mg/kg once daily for 9 days. The mice formed Control Group. A group ofmice to which TMG was administered simultaneously with ADM in a dosageof 0.1 mg/kg once daily for 9 days formed Test Group.

The time-course changes of the body weight of the Control Group and TestGroup were measured. The results are shown in Table 7.

TABLE 7 Days after start Decrease of body weight (g) of the test ControlGroup Test Group 1 1.5 2.0 3 3.3 3.1 5 5.7 4.1 7 6.5 3.0 9 — 1.5

The results of Table 7 indicate that the combined use of TMG in a smalldosage represses the decrease of body weight of mice due to theadministration of ADM and promotes recovery from the side effect.

Test of Acute Toxicity

The ameliorating agent for cancer chemotherapy of this invention wastested for acute toxicity to confirm the safety thereof. To groups eachof 3 ICR mice of 4-5 weeks, the same TMG as mentioned above wassuspended as the chromanol glycoside in a 5% gum arabic solution. Theresultant suspension was orally administered in a dosage of 500 mg/kg asreduced to TMG. For one week, the mice were kept under observation. Inthis case, to the mice of the Control Group, 0.3 ml of a 5% gum arabicsolution was orally administered. No dead mice were found in either ofthe groups used in the present test.

PREPARATION EXAMPLE 1

A dusting powder was obtained by mixing 100 g of TMG, 800 g of lactose,and 100 g of corn starch with a blender.

PREPARATION EXAMPLE 2

A granule was obtained by mixing 100 g of TMG, 450 g of lactose, and 100g of hydroxypropyl cellulose of a low degree of substitution, adding 350g of an aqueous 10% hydroxypropyl cellulose solution to the resultantmixture, kneading them, granulating the resultant blend with anextruder, and drying the resultant pellets.

PREPARATION EXAMPLE 3

A tablet was obtained by mixing 100 g of TMG, 550 g of lactose, 215 g ofcorn starch, 130 g of crystalline cellulose, and 5 g of magnesiumstearate with a blender, and molding the resultant mixture in the shapeof tablets with a tabletting device.

PREPARATION EXAMPLE 4

A capsule was obtained by mixing 100 g of TMG, 110 g of lactose, 58 g ofcorn starch, and 2 g of magnesium stearate with a V-shaped mixer, andfilling No. 3 capsules each with 180 mg of the resultant mixture.

FORMULATION EXAMPLE 5

An injection was obtained by dissolving 200 mg of TMG and 100 mg ofglucose in 2 ml of purified water, filtering the resultant solution,dispensing the filtrate in 2-ml ampoules, sealing the filled ampoules,and sterilizing the completed ampoules.

FORMULATION EXAMPLE 6

A lotion was obtained by mixing 1 g of TMG, 3 g of ethanol, 0.2 g ofhydroxyethyl cellulose, and 0.1 g of methyl paraoxybenzoate, anddissolving the resultant mixture in 100 ml of purified water.

INDUSTRIAL APPLICABILITY

The ameliorating agent for cancer chemotherapy of this invention has awater-soluble chromanol glycoside as an active ingredient thereof, asmentioned above. The use of this ameliorating agent in cancerchemotherapy results in enhancing the carcinostatic action in the cancerchemotherapy and repressing truly effectively serious side effectsmanifested in consequence of the cancer chemotherapy as well. It,therefore, enables the cancer chemotherapy to be continued while keepingthe dosage of the anti-cancer agent at a necessary level. Accordingly,the ameliorating agent of this invention is capable of deriving theefficacy of cancer chemotherapy to the fullest possible extent andrelieving a patent of his physical burden at the same time.

The invention claimed is:
 1. A composition for cancer chemotherapy,which comprises an effective amount of an anti-cancer agent and aneffective amount of a chromanol glycoside that is2-(α-D-glucopyranosyl)methyl-2,5,7,8-tetramethyl chroman-6-ol, whereinsaid anti-cancer agent is doxorubicin hydrochloride and wherein saidchromanol glycoside is an agent for repressing a side effect of saidanti-cancer agent wherein said side effect is decrease in body weight.2. The composition according to claim 1, wherein said cancer isleukemia.